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Objective To investigate the association between the use of limaprost and the risk of bleeding. Methods A self-controlled case series analysis was conducted using the National Health Insurance Service-National Sample Cohort database in South Korea. We identified patients aged 18 years or older who had at least one prescription of limaprost and were diagnosed with at least one case of bleeding between 2003 and 2019. The incidence rate ratio (IRR) of bleeding was calculated by dividing the incidence rate in the exposed period to limaprost by that in the unexposed period and adjusted for age using conditional Poisson regression model. Results Among 72,860 patients with limaprost prescriptions and bleeding diagnoses, there were 184,732 events of bleeding. After adjusting for age, the IRR was 1.47 (95% confidence interval [CI], 1.43–1.50), wherein the IRR was the highest during the 0–7 days after limaprost initiation (IRR, 2.11; 95% CI, 2.03–2.18). Risk of bleeding was higher when limaprost was concomitantly used with antithrombotics or other drugs for spinal stenosis treatment, and when higher daily doses of limaprost were administered. Conclusion Our findings suggest that the risk of bleeding increased by 1.5-fold in periods of limaprost exposure compared to unexposed periods, with particularly higher risks observed during the first week after limaprost initiation, with concomitant drugs related to bleeding, and with a higher daily dose. A careful risk-benefit assessment is warranted when initiating limaprost, especially when administered with other medications or in higher daily doses.

Objective To investigate the risk of cardiovascular events associated with commonly used dual and triple therapies of evogliptin, a recently introduced dipeptidyl peptidase-4 inhibitor (DPP4i), for managing type 2 diabetes in routine clinical practice.Design A retrospective cohort study.Setting Korean Health Insurance Review and Assessment database.Participants Patients who initiated metformin-based dual therapy and metformin+sulfonylurea-based triple therapy in South Korea from 2014 to 2018.Interventions Initiation of combination therapy with evogliptin.Primary and secondary outcome measures Hazards of cardiovascular events, a composite endpoint of myocardial infarction, heart failure and cerebrovascular events, and its individual components. Cox proportional hazards model with propensity score-based inverse probability of treatment weighting were used to estimate HRs and 95% CIs.Results From the dual and triple therapy cohorts, 5830 metformin+evogliptin users and 2198 metformin+sulfonylurea+evogliptin users were identified, respectively. Metformin+evogliptin users, as compared with metformin+non-DPP4i, had a 29% reduced risk of cardiovascular events (HR 0.71, 95% CI 0.62 to 0.82); HRs for individual outcomes were cerebrovascular events (0.71, 95% CI 0.53 to 0.95), heart failure (0.70, 95% CI 0.59 to 0.82), myocardial infarction (0.89, 95% CI 0.60 to 1.31). Metformin+sulfonylurea+evogliptin users, compared with metformin+sulfonylurea+non-DPP4i, had a 24% reduced risk of cardiovascular events (0.76, 95% CI 0.59 to 0.97); HRs for individual outcomes were myocardial infarction (0.57, 95% CI 0.27 to 1.19), heart failure (0.74, 95% CI 0.55 to 1.01), cerebrovascular events (0.96, 95% CI 0.61 to 1.51).Conclusions These findings suggest that dual or triple therapies of evogliptin for the management of type 2 diabetes in routine clinical practice present no cardiovascular harms, but could alternatively offer cardiovascular benefits in this patient population.

Abstract Background Nonpersistence in anticoagulation therapy is common and associated with undesirable clinical outcomes in patients with venous thromboembolism (VTE). Methods We investigated preceding clinical events of treatment nonpersistence (e.g., switching, discontinuing, or restarting) in VTE patients with and without active cancer using Korean claims database. Results Clinically significant events including thromboembolic events, hepatic function change and surgery preceded treatment nonpersistence, but heterogeneous distributions of clinical events were observed in the presence of active cancer. Patients with active cancer had a low rate of clinical events preceding treatment nonpersistence, and new active cancer diagnosis in the nonactive cancer group was most common before the switch to parenteral anticoagulants from warfarin or non‐vitamin K antagonist oral anticoagulants (NOACs). Conclusion These findings suggest that clinically significant events can precede treatment nonpersistence and largely paralleled current guidelines for patients with VTE, whereas heterogeneous distributions of clinical events were observed in the presence of active cancer.

Abstract Background Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE). Methods Five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel–Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates. Results Compared to trial populations, real-world study populations were older (range: 63–69 years [RWE] vs. 54–59 years [RCT]), with more females (55–60.5% vs. 39–48.3%) and had a higher prevalence of active cancer (4.2–15.4% vs. 2.5–9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70–0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37–0.96; Hokusai-VTE: 0.49, 0.31–0.78; EINSTEIN-DVT: 0.54, 0.33–0.89; EINSTEIN-PE: 0.50, 0.34–0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs. Conclusions This study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.

Abstract Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Background/Purpose(s): Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid. Methods: We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014–2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups. Results: Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42–1.27] and 0.89 [0.50–1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31–2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05–3.57]) within 6 months of treatment. Conclusion: This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.

Abstract Background Given the cumulative evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on chronic heart failure, demand is emerging for further information on their effects in patients who are hospitalized for acute heart failure. However, there is still limited evidence about the class effect of SGLT2is on acute heart failure. We investigated whether initiating treatment with SGLT2is after an episode of acute heart failure reduces the risks of post-discharge heart failure readmission or cardiovascular mortality among patients with type 2 diabetes. Methods A retrospective cohort study was conducted in a cohort of patients with type 2 diabetes who hospitalized for heart failure, using Korean Health Insurance Review & Assessment database (2015–2020). The exposure was defined as initiation of SGLT2is during hospitalization or at discharge. We assessed hazards of post-discharge heart failure readmission and cardiovascular death at 1-year, and 30-, 60-, and 90-day from the date of discharge in the SGLT2is users and non-users. Cox proportional hazards models with propensity score-based inverse probability of treatment weighting were used to estimate hazard ratios and 95% confidence intervals. Results Among 56,343 patients with type 2 diabetes hospitalized for heart failure, 29,290 patients were included in the study cohort (mean [SD] age, 74.1 [10.8] years; 56.1% women); 818 patients (2.8%) were prescribed SGLT2is during index hospitalization or at discharge. Patients with a prescription for SGLT2i vs. those without prescription had lower rates of heart failure readmission or cardiovascular death at 1 year (22.4% vs. 25.3%; adjusted hazard ratio, 0.90 [95% confidence interval, 0.87–0.93]), and also at 30 days (7.0% vs. 7.7%%; 0.74 [0.69–0.79]). Conclusions Among patients with type 2 diabetes, initiating SGLT2i treatment after an episode of acute heart failure was significantly associated with a reduced combined risk of heart failure readmission and cardiovascular mortality in a nationwide cohort reflecting routine clinical practice.

Risk factors of MDR-TB remain unclear in South Korea, despite being an important public health issue. Findings from this study, which included ≥50,000 patients with TB from South Korea, suggests that immigrants and patients with lower income levels were strong predictors of MDR-TB in a high-income, high TB incidence country.

Abstract Background Impaired respiratory function remains underrecognized in patients with type 2 diabetes (T2D), despite common pulmonary impairment. Meanwhile, there is little data available on the respiratory effects of sodium glucose cotransporter 2 inhibitors (SGLT2i). Hence, we examined the association between SGLT2i use and the risk of adverse respiratory events in a real-world setting. Methods We conducted a population-based, nationwide cohort study using an active-comparator new-user design and nationwide claims data of South Korea from January 2015 to December 2020. Among individuals aged 18 years or older, propensity score matching was done to match each new user of SGLT2is with dipeptidyl peptidase 4 inhibitors (DPP4is), with patients followed up according to an as-treated definition. The primary outcome was respiratory events, a composite endpoint of acute pulmonary edema, acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure. Secondary outcomes were the individual components of the primary outcome and in-hospital death. Cox models were used to estimate hazard ratios (HRs) and 95% CIs. Results Of 205,534 patient pairs in the propensity score matched cohort, the mean age of the entire cohort was 53.8 years and 59% were men, with a median follow-up of 0.66 years; all baseline covariates achieved balance between the two groups. Incidence rates for overall respiratory events were 4.54 and 7.54 per 1000 person-years among SGLT2i and DPP4i users, respectively, corresponding to a rate difference of 3 less events per 1000 person-years (95% CI − 3.44 to − 2.55). HRs (95% CIs) were 0.60 (0.55 to 0.64) for the composite respiratory endpoint, 0.35 (0.23 to 0.55) for acute pulmonary edema, 0.44 (0.18 to 1.05) for ARDS, 0.61 (0.56 to 0.66) for pneumonia, 0.49 (0.31 to 0.76) for respiratory failure, and 0.46 (0.41 to 0.51) for in-hospital death. Similar trends were found across individual SGLT2is, subgroup analyses of age, sex, history of comorbidities, and a range of sensitivity analyses. Conclusions These findings suggest a lower risk of adverse respiratory events associated with patients with T2D initiating SGLT2is versus DPP4is. This real-world evidence helps inform patients, clinicians, and guideline writers regarding the respiratory effects of SGLT2i in routine practice.

Background: Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. Methods: We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea’s healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1–30 day (hazard) and 61–90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratios (ORs) with 95% confidence intervals (CIs), where the relative difference in OR among the two settings was calculated to quantify the IMTB. Results: The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27; 95% CI, 1.12–1.44; pseudo-outpatient setting OR 1.21; 95% CI, 1.06–1.39; magnitude 0.05), case-time-control (OR 1.18; 95% CI, 0.98–1.44; OR 1.13; 95% CI, 0.92–1.38; 0.04, respectively), and case-case-time-control analyses (OR 0.99; 95% CI, 0.80–1.23; OR 0.94; 95% CI, 0.75–1.18; 0.05, respectively). In the mortality example, IMTB had significant impacts in the case-crossover (non-missing exposure setting OR 1.44; 95% CI, 1.36–1.52; pseudo-outpatient setting OR 0.72; 95% CI, 0.67–0.78; magnitude 1.00), case-time-control (OR 1.38; 95% CI, 1.26–1.51; OR 0.68; 95% CI, 0.61–0.76; 1.03, respectively), and case-case-time-control analyses (OR 1.27; 95% CI, 1.15–1.40; OR 0.62; 95% CI, 0.55–0.69; 1.05, respectively). Conclusion: Although IMTB had negligible impacts on the drug’s effect on acute events, as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug’s effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Abstract Upon withdrawal of propacetamol, an injectable formulation of the paracetamol prodrug, in Europe due to safety concerns, South Korea’s regulatory body requested a post-marketing surveillance study exploring its safety profile. We characterized regional disparities in adverse events (AE) associated with propacetamol between Asia and Europe using the World Health Organization’s pharmacovigilance database, VigiBase. We performed disproportionality analyses using reporting odds ratios (rOR) and information component (IC) to determine whether five AEs (anaphylaxis, Stevens–Johnson syndrome, thrombosis, contact dermatitis/eczema, injection site reaction [ISR]) were associated with propacetamol versus non-propacetamol injectable antipyretics in Asia and Europe, separately. In Asia, there was a high reporting ratio of propacetamol-related ISR (rOR 5.72, 95% CI 5.19–6.31; IC025 1.27), satisfying the signal criteria; there were no reports of thrombosis and contact dermatitis/eczema. Two signals were identified in Europe, with higher reporting ratios for thrombosis (rOR 7.45, 95% CI 5.19–10.71; IC025 1.92) and contact dermatitis/eczema (rOR 16.73, 95% CI 12.48–22.42; IC025 2.85). Reporting ratios of propacetamol-related anaphylaxis were low for Asia and Europe. While signals were found for thrombosis and contact dermatitis/eczema in Europe, these were not detected in Asia. These findings suggest potential ethnic differences in propacetamol-related AEs between Asia and Europe, which could serve as supportive data for future decision-making.

Background/Purpose(s): The World Health Organization (WHO) released treatment guidelines for multidrug resistant tuberculosis (MDR-TB) in 2008, with subsequent revisions in 2011; Korea disseminated corresponding guidelines in 2011 and 2014, respectively. Thus, we aimed to investigate the temporal trends of and the updated guideline's impact on the prescription patterns of anti-TB drugs. Methods: We conducted a time-series study using Korea's nationwide healthcare database (2007–2015), where patients with TB or MDR-TB were included. Only anti-TB drugs prescribed during the intensive phase of treatment for TB (two months) or MDR-TB (eight months) were assessed. We estimated the annual utilization of TB treatment regimens and the relative difference (RD) in the proportion of MDR-TB treatment medications between the following periods: before the first Korean guideline (June 2008 to March 2011); between the first and revised guidelines (April 2011 to July 2014); after the revised guideline (August 2014 to December 2015). Results: Of 3523 TB (mean age 54.1 years; male 56.8%) patients, treatment regimens for TB complied with guideline recommendations as >80% of patients received either quadruple (mean 66.8%) or triple (14.5%) therapy of first-line anti-TB drugs. Following the WHO's guideline update, prescription patterns changed accordingly among 111 MDR-TB (mean age 46.0 years; male 67.6%) patients, as use of pyrazinamide (RD +20.3%) and prothionamide (+11.5%) increased (recommended to be compulsory), and streptomycin (−43.1%) decreased (ototoxicity risks). Conclusions: Anti-TB drug prescription patterns for both TB and MDR-TB well reflected WHO's treatment guideline as well as corresponding domestic guidelines of South Korea.

BackgroundExisting data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes.Methods and findingsWe conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors.ConclusionsThis large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for

Background In South Korea, women aged 66 years are eligible for complimentary bone mineral density (BMD) screening via the National Screening Program for Transitional Ages. We aimed to evaluate the 10-year fracture risk in women receiving BMD screening between January 2008 and December 2015. Methods BMD was classified as normal (T-score ≥−1.0 standard deviation [SD]), osteopenia (T-score −2.5 SD), and osteoporosis (T score ≤−2.5 SD) from dual-energy X-ray absorptiometry. Follow-up continued from the screening date until a diagnosis for clinical fragility fracture (including sites of the vertebrae, hip, pelvis, clavicle, humerus, forearm, wrist, lower leg, and ankle), censored at the earliest date of trauma, death, or December 2017; fracture was ascertained using diagnostic codes from the National Health Insurance Service database. A multivariable Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of fracture in women with osteopenia or osteoporosis relative to women with normal BMD. Results Among the 271,197 women screened, 44.0% had osteopenia and 35.2% had osteoporosis. The 10 year cumulative incidence of fragility fractures was 31.1%, 37.5%, and 44.3% in women with normal BMD, osteopenia, and osteoporosis, respectively. Fracture risk was higher in women with osteopenia (HR, 1.31; 95% CI, 1.28 to 1.34) and osteoporosis (HR, 1.68; 95% CI, 1.64 to 1.72) than in women with normal BMD. Conclusion Women with osteopenia and women with osteoporosis, identified by the national BMD screening program, demonstrated a substantially elevated risk of fracture.

Anticoagulants are a potential treatment for the thrombotic complications resulting from COVID-19. We aimed to determine the association between anticoagulant use and adverse outcomes among hospitalized patients with COVID-19. We used data from the COVID-19 International Collaborative Research Project in South Korea from January to June 2020. We defined exposure using an intention-to-treat approach, with person-time classified as use or non-use of anticoagulants at cohort entry, and a time-varying approach. The primary outcome was all-cause, in-hospital mortality; the secondary outcome was a composite including respiratory outcomes, cardiovascular outcomes, venous thromboembolism, major bleeding, and intensive care unit admission. Cox proportional hazards models estimated adjusted hazard ratios (HRs) of the outcomes comparing use versus non-use of anticoagulants. Our cohort included 2,677 hospitalized COVID-19 patients, of whom 24 received anticoagulants at cohort entry. Users were older and had more comorbidities. The crude incidence rate (per 1,000 person-days) of mortality was 5.83 (95% CI: 2.80, 10.72) among anticoagulant users and 1.36 (95% CI: 1.14, 1.59) for non-users. Crude rates of the composite outcome were 3.20 (95% CI: 1.04, 7.47) and 1.80 (95% CI: 1.54, 2.08), respectively. Adjusted HRs for mortality (HR: 1.12, 95% CI: 0.48, 2.64) and the composite outcome (HR: 0.79, 95% CI: 0.28, 2.18) were inconclusive. Although our study was not able to draw conclusions on anticoagulant effectiveness for COVID-19 outcomes, these results can contribute to future knowledge syntheses of this important question. Our study demonstrated that the dynamic pandemic environment may have important implications for observational studies of COVID-19 treatment effectiveness.

Abstract Background With antidepressants (ADs) having minimal therapeutic effects during the initial weeks of treatment, benzodiazepines (BZDs) are concomitantly used to alleviate depressive symptoms of insomnia or anxiety. However, with mortality risks associated with this concomitant use yet to be examined, it remains unclear as to whether this concomitant therapy offers any benefits in treating depression. Methods We conducted a population-based cohort study using South Korea’s nationwide healthcare database from 2002 to 2017. Of 2.6 million patients with depression, we identified 612,729 patients with incident depression and newly prescribed ADs or BZDs, by excluding those with a record of diagnosis or prescription within the 2 years prior to their incident diagnosis. We classified our study cohort into two discrete groups depending on the type of AD treatment received within 6 months of incident diagnosis—AD monotherapy and AD plus BZD (AD+BZD) therapy. We matched our study cohort in a 1:1 ratio using propensity scores to balance baseline characteristics and obtain comparability among groups. The primary outcome was all-cause mortality, and patients were followed until the earliest of outcome occurrence or end of the study period. We conducted multivariable Cox proportional hazards regression analysis to estimate adjusted hazards ratios (HRs) with 95% confidence intervals (CIs) for the risk of mortality associated with AD+BZD therapy versus AD monotherapy. Results The propensity score-matched cohort had 519,780 patients with 259,890 patients in each group, where all baseline characteristics were well-balanced between the two groups. Compared to AD monotherapy, AD+BZD therapy was associated with an increased risk of all-cause mortality (adjusted HR, 1.04; 95% CI, 1.02 to 1.06). Conclusions Concomitantly initiating BZDs with ADs was associated with a moderately increased risk of mortality. Clinicians should therefore exercise caution when deciding to co-prescribe BZDs with ADs in treating depression, as associated risks were observed.

Introduction Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records.Methods and analysis This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported.Ethics and dissemination Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.

OBJECTIVES This study explored socioeconomic disparities in Korea using health insurance type as a proxy during the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS We conducted a retrospective cohort study using Korea’s nationwide healthcare database, which contained all individuals who received a diagnostic test for COVID-19 (n=232,390) as of May 15, 2020. We classified our cohort by health insurance type into beneficiaries of the National Health Insurance (NHI) or Medicaid programs. Our study outcomes were infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19-related outcomes, a composite of all-cause death, intensive care unit admission, and mechanical ventilation use. We estimated age-, sex-, and Charlson comorbidity index score–adjusted odds ratios (aORs) with 95% confidence intervals (CIs) using a multivariable logistic regression analysis. RESULTS Of the 218,070 NHI and 14,320 Medicaid beneficiaries who received COVID-19 tests, 7,777 and 738 tested positive, respectively. The Medicaid beneficiaries were older (mean age, 57.5 vs. 47.8 years), more likely to be males (47.2 vs. 40.2%), and had a higher comorbidity burden (mean CCI, 2.0 vs. 1.7) than NHI beneficiaries. Compared to NHI beneficiaries, Medicaid beneficiaries had a 22% increased risk of SARS-CoV-2 infection (aOR, 1.22; 95% CI, 1.09 to 1.38), but had no significantly elevated risk of COVID-19-related outcomes (aOR 1.10, 95% CI 0.77 to 1.57); the individual events of the composite outcome yielded similar findings. CONCLUSIONS As socioeconomic factors, with health insurance as a proxy, could serve as determinants during the current pandemic, pre-emptive support is needed for high-risk groups to slow its spread.

Therapeutic ineffectiveness involves drug-related therapeutic failure, inefficacy or resistance and has not been sufficiently studied. Objective of our study was to evaluate reporting trends in therapeutic ineffectiveness by year and describe factors affecting therapeutic ineffectiveness using the Korea Adverse Event Reporting System. Proportion of therapeutic ineffectiveness reports was based on total submitted reports between 2000 and 2016. Utilizing 2016 alone, we compared the characteristics of therapeutic ineffectiveness with age group and gender matching by random extraction. We conducted a logistic regression analysis to estimate reporting odds ratios (ROR) and its 95% confidence intervals (CI) for reports by type of reporters, e.g., doctors, pharmacists, or consumers. We presented most frequent reports by the anatomical main groups and therapeutic subgroups according to the Anatomical Therapeutic Chemical (ATC) classification system. For the 17-years, the proportion of therapeutic ineffectiveness adverse drug reactions reporting ranged from 0.0% to 3.7% between 2000 and 2016. Of 228,939 reports, 2,797 (1.2%) were submitted in 2016. Consumers accounted for 6.92% of reports and doctors accounted for 45.49%, in which, consumers were more likely to report therapeutic ineffectiveness than doctors (adjusted ROR 3.98; 95% CI, 2.92 to 5.41). According to the ATC classification system, "nervous system" was the most frequently reported anatomical group (18.7%) and "parathyroid hormones and analogues" was reported most frequently in the pharmacological subgroup (23.7%). Teriparatide, a drug used to treat osteoporosis, had the most reports (11.0%). Therapeutic ineffectiveness reports may be used as a scientific tool for the reevaluation of respective drugs in order to confirm of its therapeutic effects.

Rheumatoid arthritis (RA) and allergic diseases are result of a poor functioning immune system, giving dominance to either T-helper 1 (Th1) or T-helper 2 (Th2) diseases, respectively. Studies have stated that there seems to be a relationship present between the immune response subsets. This study was designed to examine the association between RA and respiratory allergic diseases in Korean adults. The study utilized the KNHANES 2013–2015 data and excluded individuals diagnosed with RA before being diagnosed with allergic diseases, using age at clinical diagnosis. Total of 253 RA patients were matched 1 : 1 with non-RA patients by a propensity score, using sex and age as matched variables. Multivariate conditional logistic regression analyses were used to evaluate for association between RA and respiratory allergic diseases in the matched 506 participants. RA was associated with an increased risk of prevalence of respiratory allergic diseases with an OR of 1.51 (95% CI, 1.31–1.75), adjusted for socioeconomic demographic variables. The adjusted OR for prevalence of RA among participants with prevalence of asthma and allergic rhinitis was as follows: 3.12 (95% CI, 2.77–3.51) and 1.39 (95% CI, 1.16–1.67). Participants with prevalence of asthma in particular had an increased risk of developing prevalence of RA. Based on our findings, Th1 and Th2 diseases may indeed coexist, and one pathway may stimulate or contribute towards the onset of the other.

Purpose: Following the withdrawal of propacetamol in Europe owing to safety issues, the regulatory authority of South Korea requested a post-marketing surveillance study to investigate its safety profile. Materials and Methods: We conducted nested case-control and case-time-control (CTC) analyses of cases and controls identified for outcomes of interest, including anaphylaxis, thrombosis, and Stevens--Johnson syndrome (SJS), using the claims database of South Korea, 2010--2019. Risk-set sampling was used to match each case with up to 10 controls for age, sex, cohort entry date, and follow-up duration. Exposure to anaphylaxis, thrombosis, and SJS was assessed within 7, 90, and 30 days of the index date, respectively. We calculated odds ratios (OR) with 95% confidence intervals (CIs) using conditional logistic regression to assess the risk of outcomes associated with propacetamol. Results: We identified cases of anaphylaxis (n=61), thrombosis (n=95), and SJS (n=1) and matched them to controls (173, 268, and 4, respectively). In the nested case-control analysis, the ORs for anaphylaxis and SJS were inestimable given the small number of propacetamol users during the risk period; meanwhile, the OR for thrombosis was 1.60 (95% CI 0.71--3.62). In the CTC design, the effect estimate was only estimated for thrombosis (OR 0.56, 95% CI 0.09--3.47). Conclusion: In both nested case-control and CTC analyses, propacetamol was not associated with an increased risk of anaphylaxis, thrombosis, or SJS. The findings from this study, which used routinely collected clinical data, provide reassuring real-world evidence regarding the safety of propacetamol in a nationwide population to support regulatory decision-making. [ABSTRACT FROM AUTHOR]